In 1952, Hodgkin and Huxley showed that the main body of neural activity is an Na channel, after which Na channel blockers have been developed as antiarrhythmic or topical anesthetics. In 1961, lidocain, which is one of the Na channel blockers, was found to provide an analgesic effect, and clinical application thereof as an analgesic was started. However, since Na channel is also present in nonneural tissues such as muscle, heart and the like, side effects by systemic administration remained as a problem.
With the advance of molecular biology, subtypes of Na channel have been elucidated one after another, and Na channel α subunit that forms pore is known to include 10 kinds at present. A sensory neuron specific sodium channel (sensory nerve-specific Na channel), i.e., SNS, is one of such Na channel α subunits, is a tetrodotoxin (TTX)-resistant Na channel localized in the small diameter cell (C fiber) of dorsal root ganglion involved in nerval perception, and is also called SCN10A, PN3 or NaV1.8 (non-patent documents 1, 2). It has been reported that SNS knockout mouse is insensitive to mechanical stimulations, and administration of antisense to SNS to neuropathic pain or inflammatory pain models attenuates hypersensitivity and abnormal perception.
Therefore, an SNS inhibitor is considered to provide a therapeutic or prophylactic drug showing an analgesic effect for diseases such as neuropathic pain, nociceptive pain and the like, which accompany pain, numbness, burning sensation, dull pain and the like, each involving C fiber. Moreover, since SNS is not expressed in nonneural tissues and central nervous system, a medicament that selectively inhibits SNS is considered to be a medicament free of side effects derived from nonneural tissues or central nervous system.
In dysuria, moreover, it has been clarified that frequent urination, its main symptom, is caused by overactivity of the C fiber; in other words, dysfunction of afferent sensory nervous pathway from the lower urinary tract is involved in overactive bladder and cystalgia, and suppression of C fiber sensory nerve from the bladder is effective thereon (non-patent document 3). Therefore, a medicament that inhibits SNS mainly causing the neural activity of C fiber is expected to be a therapeutic or prophylactic drug for dysuria, which has a novel point of action.
On the other hand, a recent report has documented that SNS found only in C fiber is ectopically expressed in cerebellar Purkinje cell of multiple sclerosis patients, and is involved in the occurrence of an abnormal firing pattern in the cerebellum (non-patent document 4). As such, an SNS inhibitor is expected to be a first therapeutic or prophylactic drug toward the induction of symptoms caused by abnormal firing associated with SNS expression in the cerebellar neuron, such as ataxia and the like in multiple sclerosis.
The following shows the actual treatment state of the aforementioned diseases in clinical practice.
(1) Neuropathic Pain
Neuropathic pain refers to a pain including spontaneous pain and chronic pain developed by nerve damage or nerve stimulation even when trauma is absent and tissue inflammation is absent after complete recovery. Examples thereof include neuralgia after lumbar operation, diabetic neuropathy, neuralgia after herpes zoster, reflex sympathetic dystrophy, phantom limb pain, spinal cord damage, late stage carcinomatous pain, and prolonged postoperative pain. NSAIDS (non-steroidal anti-inflammatory drugs) such as aspirin and the like are completely ineffective for neuropathic pain, and opioids such as morphine and the like are problematic in drug resistance and induction of psychological symptom.
At present, a sole medicament in the market, which is allegedly effective for neuropathic pain, is mexiletine applicable to diabetic neuropathy. Since mexiletine does not have selectivity to Na channel, though it provides an analgesis effect, side effects are feared and administration at a high dose has been reported to be unavailable. Some other medicaments are clinically applied as aids. Examples thereof include antidepressant (sulpiride, trazodone, fluvoxatine, milnacipran), adrenaline agonist (clonidine, dexmedetomidine), NMDA receptor antagonists (ketamine hydrochloride, dextromethorphan), antianxiety drug (diazepam, lorazepam, etizolam, hydroxyzine hydrochloride), anticonvulsant (carbamazepine, phenyloin, sodium valproate, zonisamide), calcium antagonist (nifedipine, verapamil hydrochloride, lomerizine hydrochloride) and the like, all of which are used as aids. From the above, a therapeutic drug free of side effects derived from nonneural tissue or central nervous system and specifically effective for pain is desired.
(2) Nociceptive Pain
Nociceptive pain refers to a pain caused by the activation of nociceptor (Aδ, C fiber) by mechanical, hyperthermic or chemical noxious stimulation due to tissue injury and the like. Nociceptor is sensitized by endogenous chemical stimulation (algetic substance) such as serotonin, substance P, bradykinin, prostaglandin and histamine. Examples of the nociceptive pain include lumbago, abdominal pain, and pain due to rheumatoid arthritis or osteoarthritis. In clinical practice, NSAIDS (acetylsalicylic acid, acetaminophen, diclofenac sodium, indomethacin, mofezolac, flurbiprofen, loxoprofen sodium, ampiroxicam), steroid drugs (prednisolone, methylprednisolone, dexamethasone, betamethasone), PGE1 (prostaglandin E1) (alprostadil, lipo alprostadil, limaprost alprostadil) and PGI2 (beraprost sodium) are used.
(3) Dysuria (Urinary Disturbance)
Dysuria is a disease mainly showing urinary frequency, urorrhea, feeling of residual urine and urodynia as main symptoms. At present, the main drug treatment of overactive bladder uses a muscarinic receptor inhibitor that suppresses the bladder parasympathetic nerve pathway. However, its limitation has also been clarified. Capsaicin and resinifera toxin, which are vanilloid receptor stimulants, have been reported to specifically act on C fiber to suppress its function. However, a medicament that acts on SNS localized in C fiber has not been found.
(4) Multiple Sclerosis
Multiple sclerosis is one kind of demyelination diseases, which shows scattered foci of demyelination in the white matter of the central nervous system, with various old and new lesions. The lesions appear more commonly in the white matter of lateral cerebral ventricle periphery, optic nerve, brain stem, spinal cord and the like. Histologically, myelin sheath is destroyed and axon and nerve cell are not damaged. As clinical symptoms, symptoms such as optic neuritis, double vision, eyeball motion impairments such as nystagmus, convulsive paralysis, painful tonic convulsive attack, Lhermitte's syndrome, ataxia, logopathy, bladder rectal disorder and the like appear in various combinations. The etiology thereof is unknown, though autoimmune disease theory, infection theory and the like are proposed. At present, an effective prophylactic or therapeutic drug for multiple sclerosis is highly desired.
Patent document 1 to be mentioned later relates to a selective modulator of CRF1 receptor and specifically describes a compound represented by the following formula (A) (Example 5, k). The compounds encompassed in the patent document characteristically have an amide bond in methylene on the imidazole ring, and are different from the compound of the present invention having an amino group in methylene on the imidazole ring. In addition, patent document 1 does not at all contain a description suggesting the present invention.

Patent document 2 to be mentioned later relates to a Rho kinase inhibitor, and specifically describes a compound represented by the following formula (B) (Example 321). The compounds encompassed in the patent document do not have a substituent on the nitrogen atom of imidazole ring, and are different from the compound of the present invention essential having the substituent. In addition, patent document 2 does not at all contain a description suggesting the present invention.
